Derivation of a Pharmacophore Model for Anandamide Using Constrained Conformational Searching and Comparative Molecular Field Analysis

Abstract

Constrained molecular dynamics simulations on anandamide, together with a systematic distance comparison search, have revealed a specific low-energy conformer whose spatial disposition of the pharmacophoric elements closely matches that of HHC. This conformer enables near superposition of the following: (1) the oxygen of the carboxyamide and the phenolic hydroxyl group of HHC, (2) the hydroxyl group of the ethanol and the cyclohexyl hydroxyl group of HHC, (3) the alkyl tail and the lipophilic side chain of HHC, and (4) the polyolefin loop and the tricyclic ring structure of HHC. The close matching of common pharmacophoric elements of anandamide with HHC offers persuasive evidence of the biological relevance of this conformer. The proposed pharmacophore model was capable of discriminating between structurally related compounds exhibiting different pharmacological potency for the CB1 cannabinoid receptor, i.e., anandamide and N-(2-hydroxyethyl)prostaglandinamide. Furthermore, a 3D-QSAR model was derived using CoMFA for a training set of 29 classical and nonclassical analogues which rationalized the binding affinity in terms of steric and electrostatic properties and, more importantly, which predicted the potency of anandamide in excellent agreement with experimental data. The ABC tricyclic HU-210/HU-211 and ACD tricyclic CP55,243/CP55,244 enantiomeric pairs were employed as test compounds to validate the present CoMFA model. For each enantiomeric pair, the CoMFA-predicted log Ki values correctly identified that enantiomer exhibiting the higher affinity for the receptor.

Endogenous Unsaturated C18 N-Acylethanolamines Are Vanilloid Receptor (TRPV1) Agonists

“…A similar low energy helical conformation of anandamide has been reported previously using computational methods (36). As shown previously, the cannabinoid CB 1 receptor recognizes NAEs with fatty acid chains having at least (i) three homoallylic double bonds and (ii) five terminal unsaturated carbons (25).…”

Oxygenated Metabolites of Anandamide and 2-Arachidonoylglycerol: Conformational Analysis and Interaction with Cannabinoid Receptors, Membrane Transporter, and Fatty Acid Amide Hydrolase

“…To investigate whether the introduction of the 1-hydroxy-2E,4Z-pentadiene system in AEA influenced the orientation and distances of pharmacophoric groups in the HAEAs, the pharmacophores of the reference compound CP-55,940 were compared with pharmacophores in the (H)AEA series ( Figure 5). The pharmacophoric groups were identified based on the model of Tong et al 25 This model was capable of discriminating between structurally related compounds exhibiting different pharmacological potencies for the CB 1 receptor, i.e., AEA and prostaglandinethanolamide. Furthermore, it could be used in a three-dimensional quantitative structure-activity relationship (3D QSAR) study to predict the K i value of AEA.…”

“…Furthermore, the cyclohexyl OH in the cannabinoids and the corresponding terminal OH of AEA both enhance binding, but their absence (as in THC and alkyl arachidonate derivatives) does not eliminate activity. 25 First, the conformation of CP-55,940 was analyzed to find the orientation of the hexyl ring in relation to the phenyl ring, and the orientation of the alkyl side chain. NOESY data for CP-47,497 (in chloroform) have shown that the orientation of the two rings around the C 6 -C 7 bond, determined by the dihedral angle C 5 -C 6 -C 7 -C 8 (see Figure 5 for numbering), is -60°rather than 120°.…”

“…This region is scarcely populated for 5R-HAEA and 5S-HAEA, and not at all for 15S-HAEA and 11S-HAEA. It is tempting to suggest a preference for analogous orientations of the pentyl tail for AEA and 12S-HAEA, which have a similar affinity for the CB 1 receptor, while the low 25 Stereospecificity is important, as indicated by differences in activity of the enantiomers 5R-HAEA and 5S-HAEA. To take this stereospecificity into account, a minimum of four atom positions has to be restrained.…”

“…Therefore, a structural comparison of active and inactive classical and synthetic cannabinoids has been used to derive pharmacophore models. [23][24][25] These models might also be used to predict and facilitate the design of novel compounds with greater potency or selectivity at the molecular target of interest. [23][24][25][26] A prerequisite for the building of such a pharmacophore model is to characterize an ensemble of active conformations of a molecule.…”